We seek to answer two questions: how do neurons become connected during development, and why do they become disconnected during neurodegenerative disease? There is a great deal of interest in developing models of neurodegenerative diseases in simple, invertebrate model systems that provide unequaled experimental power for characterizing the cellular events of a complex process and establishing its molecular genetic basis. Use of Drosophila for studies of neurodegeneration have been problematic, however, since in most cases it has either relied on highly artificial manipulations, such as high-level expression of mutated human genes in the fly, or has identified genes that clearly affect neuronal survival in the fly but are not related to genes and pathways demonstrated to play a role in neurodegeneration in mammals. We have now identified a natural, adult-onset neurodegenerative syndrome of Drosophila in flies mutant for the ortholog of a gene directly implicated in human diseases including Alzheimer Disease, Parkinson and ALS. The protein kinase Cdk5, together with its regulatory subunit, p35, is one of the major kinases that phosphorylates cytoskeletal proteins to generate the neurofibrillary tangles that are characteristic of the "tauopathy" class of neurodegenerative diseases. Moreover, activated Cdk5 is found concentrated in degenerating tissue in the brains of Alzheimer patients, and experimental activation or inactivation of Cdk5 induces degenerating lesions in the mouse brain. We have now generated a null mutation of the gene encoding the fly homolog of the Cdk5 activating subunit, p35, and find that it causes adult-onset neurodegeneration of a specific portion of the Drosophila brain, the "mushroom bodies" that are the seat of learning and memory. In the past year, we have shown that the neurodegeneration that occurs in p35 mutants has many of the classic hallmarks familiar from Cdk5-associated degenerative diseases in humans. These include gross atrophy of brain tissue, increased neuronal sensitivity to necrotic stimuli, accumulation of aggregated depositions of cellular material, axonal swellings, and increase in the number of autophagic organelles suggestive of a defect in the autophagic process. Moreover, these cellular findings are associated with progressive loss of adult motor function and a 50% reduction in lifespan. These results validate Drosophila Cdk5 as an appropriate model for studying the cellular and molecular basis of the related human diseases. Given this validation, we have moved on to exploit the Cdk5/p35 model to attack one of the great roadblocks in our understanding of human neurodegeneration: what are the first things that go wrong in the brain that initiate the inexorable progression to degeneration? We know some of the triggers that precede disease - accumulation of amyloid plaques or synuclein aggregates but what are the targets of those triggers that actually initiate the disease process itself? Taking advantage of the Drosophila system we have moved back in time to those initiating events and found two completely unexpected phenotypes. First, we found that Cdk5 is essential for both the development and maintenance of the portion of an axon where nerve impulses are initiated. Improper organization of this cellular compartment is expected to cause profound defects in the ability of a nerve cell to act in a neural circuit. There is extensive evidence for compromised neuronal function in degenerating neurons, and indeed, all the current medications for treating MCI and early stage AD act by stimulating the electrical activity of neurons. It has never been clear, however, whether activity deficits in neurons are cause or consequence of the degenerative process. Our data strongly suggest that loss of proper circuit function of affected neurons is one of the earliest events in the progression to degeneration. Second, we found that Cdk5 controls the machinery responsible for the genetically-programmed disassembly of axons and dendrites at particular developmental stages. That developmental process has many morphological and mechanistic similarities to the disassembly that occurs in the degenerating nervous system, but again, it had not been anticipated that active, large-scale disassembly of axons and dendrites would be such an early and explicit target of the machinery of neuronal maintenance. The discoveries we have made using the fly system were not predicted by any of the experiments that have been done in mammals, but our results are fully consistent with what has been done in those systems. These results therefore open up wholly new areas for investigation in determining the mechanisms responsible for human neurodegenerative disease.